Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/94—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• This invention relates to small molecules that are useful in the treatment of abnormal cell growth, such as cancer, in mammals.
• This invention also relates to a method of using such small molecules in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
• the invention further relates to small molecules, which are potent and highly selective for the erbB2 tyrosine kinase receptor over its homologous family member, the erbB1 tyrosine kinase receptor.
• a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e., a gene which, on activation, leads to the formation of malignant tumor cells).
• oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation.
• the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
• Receptor tyrosine kinases are enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation.
• Receptor tyrosine kinases include c-erbB-2 (also known as erbB2 or HER2), c-met, tie-2, PDGFr, FGFr, VEGFR and EGFR (also known as erbB1 or HER1).
• kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, ovarian, bronchial or pancreatic cancer. More particularly, it has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
• EGFR epidermal growth factor receptor
• inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells.
• erbstatin a tyrosine kinase inhibitor
• EGFR epidermal growth factor receptor tyrosine kinase
• the compounds of the present invention which are selective inhibitors of certain receptor tyrosine kinases, are useful in the treatment of abnormal cell growth, in particular cancer, in mammals.
• EP 0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1(published Jun. 22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1 (published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30, 1992), refer to certain bicyclic derivatives, in particular quinazoline derivatives, as possessing anti-cancer properties that result from their tyrosine kinase inhibitory properties. Also, World Patent Application WO 92/20642 (published Nov.
• EGFR family consists of four closely related receptors, identified as EGFR (erbB1), erbB2 (HER2), erbB3 (HER3) and erbB4 (HER4). It has also been found that the erbB2 receptor is overexpressed in human breast cancer and ovarian cancer (Slamon et al., Science, Vol. 244, pages 707-712, 1989). The erbB2 receptor is also highly expressed in a number of other cancers, such as prostate cancer (Lyne et al., Proceedings of the American Association for Cancer Research, Vol.
• the ability of a small molecule to discriminate between the erbB2 and erbB1 receptor may minimize or eliminate the occurrence of adverse events observed in clinical trials. This would provide a dramatic improvement in the art.
• the disfiguring nature of the rash may lead to poor compliance in chemotherapy treatment.
• Herceptin provided a means of treating patients in need of erbB2-related therapies with an agent that avoids this erbB1-related dermal toxicity, there are significant drawbacks to this agent that limit its utility and general applicability.
• Herceptin carries a “Black Box” warning relating to cardiomyopathy and hypersensitivity reactions including anaphylaxis. These later events are related to the fact that Herceptin is an antibody.
• Gazit et al. in the Journal of Medicinal Chemistry, 1991, vol., 34, pages 1896-1907, refer to a number of tyrphostins, which were found to discriminate between the erbB1 receptor tyrosine kinase and erbB2 receptor tyrosine kinase.
• the vast majority of the compounds referred to in Gazit et al. were selective for the erbB1 receptor over the erbB2 receptor.
• the compounds identified by Gazit were not particularly potent for either the erbB1 or erbB2 receptor. More recently, WO 00/44728 (published Aug. 3, 2000) and WO 01/77107 (published Oct.
• erbB2 inhibitors which are able to selectively inhibit erbB2 over the other members of the erbB family, and in particular erbB1.
• the inventors of the present invention now provide small molecules, which are both potent and highly selective inhibitors of erbB2 receptor tyrosine kinase over the erbB1 receptor tyrosine kinase.
• the present invention relates to a small molecule erbB2 inhibitor, wherein said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 50-1500.
• the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 60-1200.
• the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 80-1000.
• the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 90-500.
• the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 100-300. In the most preferred embodiment of the present invention the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 110-200.
• the erbB2 inhibitor has an IC 50 of less than about 100 nM. In a more preferred embodiment of the present invention the erbB2 inhibitor has an IC 50 of less than about 50 nM.
• the small molecule erbB2 inhibitor is selected from the group consisting of:
• the erbB2 inhibitor is selected from the group consisting of:
• the present invention also relates to a small molecule erbB2 inhibitor, wherein said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 50-1500 and inhibits growth of tumor cells which overexpress erbB2 receptor in a patient treated with a therapeutically effective amount of said erbB2 inhibitor.
• the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 60-1200 and inhibits growth of tumor cells which overexpress erbB2 receptor in a patient treated with a therapeutically effective amount of said erbB2 inhibitor.
• the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 90-500 and inhibits growth of tumor cells which overexpress erbB2 receptor in a patient treated with a therapeutically effective amount of said erbB2 inhibitor.
• the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 100-300 and inhibits growth of tumor cells which overexpresses erbB2 receptor in a patient treated with a therapeutically effective amount of said erbB2 inhibitor.
• the erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 110-200 and inhibits growth of tumor cells which overexpresses erbB2 receptor in a patient treated with a therapeutically effective amount of said erbB2 inhibitor.
• the present invention also relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a small molecule erbB2 inhibitor that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 50-1500.
• the present invention relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a small molecule erbB2 inhibitor that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 60-1200.
• the present invention relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a small molecule erbB2 inhibitor that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 90-500.
• the present invention relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a small molecule erbB2 inhibitor that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 100-300.
• the present invention relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal an amount of a small molecule erbB2 inhibitor that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 110-200.
• the present invention further relates to a method for the treatment of abnormal cell growth in a mammal comprising administering to said mammal an amount of an erbB2 inhibitor compound, which is selective for erbB2 over erbB1, that is effective in treating abnormal cell growth.
• the abnormal cell growth is cancer.
• the cancer is selected is selected from lung cancer, non small cell lung (NSCL), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvi
• the said cancer is selected from colon cancer, breast cancer or ovarian cancer.
• Another embodiment of the present invention relates to method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of an erbB2 inhibitor, wherein said erbB2 inhibitor is selective for erbB2 over erbB1, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
• an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
• a preferred embodiment invention relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of an erbB2 inhibitor, wherein said erbB2 inhibitor is selective for erbB2 over erbB1, that is effective in treating abnormal cell growth in combination in combination with a cytotoxic.
• the cytotoxic is Taxol® (paclitaxel).
• the present invention further relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of claim 1 that is effective in treating abnormal cell growth in combination with a compound selected from the group consisting of Cyclophosphamide, 5-Fluorouracil, Floxuridine, Gemcitabine, Vinblastine, Vincristine, Daunorubicin, Doxorubicin, Epirubicin, Tamoxifen, Methylprednisolone, Cisplatin, Carboplatin, CPT-11, gemcitabine, paclitaxel, and docetaxel.
• the invention relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of claim 1 that is effective in treating abnormal cell growth in combination with a compound selected from the group consisting Tamoxifen, Cisplatin, Carboplatin, paclitaxel and docetaxel.
• the invention further relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal comprising an amount of an erbB2 inhibitor, which is selective for erbB2 over erbB1, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
• the present invention also relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal a small molecule erbB2 inhibitor in an amount that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 50-1500 as measured by an in vitro cell assay.
• the present invention also relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal a small molecule erbB2 inhibitor in an amount that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 60-1200 as measured by an in vitro cell assay.
• the present invention also relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal a small molecule erbB2 inhibitor in an amount that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 80-1000 as measured by an in vitro cell assay.
• the present invention also relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal a small molecule erbB2 inhibitor in an amount that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 90-500 as measured by an in vitro cell assay.
• the present invention also relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal a small molecule erbB2 inhibitor in an amount that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 100-300 as measured by an in vitro cell assay.
• the present invention also relates to a method of treating abnormal cell growth in a mammal comprising administering to said mammal a small molecule erbB2 inhibitor in an amount that is effective in treating abnormal cell growth and said erbB2 inhibitor has a range of selectivities for erbB2 over erbB1 between 110-200 as measured by an in vitro cell assay.
• This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of an erbB2 inhibitor, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth.
• the abnormal cell growth is cancer, including, but not limited to, non small cell lung (NSCL) cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of
• NSC non small
• This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of an erbB2 inhibitor, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
• an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
• This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of an erbB2 inhibitor, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
• said abnormal cell growth is cancer, including, but not limited to, lung cancer, non small cell lung (NSCL), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma
• the invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of an erbB2 inhibitor, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating abnormal cell growth in combination with a pharmaceutically acceptable carrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
• an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
• the invention also relates to a method for treating a mammal having cancer characterized by an overexpression of erbB2, comprising administering to the mammal a small molecule erbB2 inhibitor in an amount that is effective in treating said cancer characterized by the overexpression of erbB2, and said erbB2 inhibitor is selective for erbB2 over erbB1 at any of the ratios and with any of the IC 50 identified herein.
• the invention also relates to a method for treating a mammal having a disease characterized by an overexpression of erbB2, comprising administering to the mammal a small molecule erbB2 inhibitor in an amount that is effective in treating a disease characterized by the overexpression of erbB2, and said erbB2 inhibitor is selective for erbB2 over erbB1 at any of the ratios and with any of the IC 50 identified herein.
• the invention also relates to a method inducing cell death comprising exposing a cell which overexpresses erbB2 to an effective amount of an erbB1-sparing erbB2 inhibitor.
• the cell is a cancer cell in a mammal, preferably a human.
• the present invention relates to a method inducing cell death comprising exposing a cell which overexpresses erbB2 to an effective amount of an erbB1-sparing erbB2 inhibitor and said method further comprises exposing the cell to a growth inhibitory agent.
• the cell is exposed to a chemotherapeutic agent or radiation.
• the invention further relates to a method of treating cancer in a human, wherein the cancer expresses the erbB2 receptor, comprising administering to the human a therapeutically effective amount of an erbB2 inhibitor that has reduced affinity for the erbB1 receptor.
• the cancer is not characterized by overexpression of erbB1 receptor.
• the cancer is characterized by overexpression of the erbB1 and erbB2 receptor.
• This invention also relates to a method for the treatment of a disorder associated with angiogenesis in a mammal, including a human, comprising administering to said mammal an amount of an erbB2 inhibitor, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, that is effective in treating said disorder.
• This invention also relates to a method of (and to a pharmaceutical composition for) treating abnormal cell growth in a mammal which comprise an amount of an erbB2 inhibitor, as defined above, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth.
• Anti-angiogenesis agents such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II ) inhibitors, can be used in conjunction with an amount of an erbB2 inhibitor, as defined above, in the methods and pharmaceutical compositions described herein.
• useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
• Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar.
• MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1.
• MMP-2 and/or MMP-9 are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
• MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13 are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
• erbB2 compounds as defined above, and the pharmaceutically acceptable salts, solvates and prodrugs thereof, can also be used in combination with signal transduction inhibitors, such as VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of South San Francisco, Calif., USA).
• signal transduction inhibitors such as VEGF (vascular endothelial growth factor) inhibitors
• erbB2 receptor inhibitors such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTINTM (Genentech, Inc. of South San Francisco, Calif., USA).
• VEGF inhibitors for example SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), can also be combined with a erbB2 compound as defined above.
• VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No.
• ErbB2 receptor inhibitors such as GW-282974 (Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), may be administered in combination with a compound of formula 1.
• erbB2 inhibitors include those described in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No.
• antiproliferative agents that may be used with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following U.S. patent applications Ser. Nos.: 09/221946 (filed Dec. 28, 1998); 09/454058 (filed Dec. 2, 1999); 09/501163 (filed Feb. 9, 2000); 09/539930 (filed Mar. 31, 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed Aug. 26, 1999); and 09/383755 (filed Aug. 26, 1999); and the compounds disclosed and claimed in the following U.S.
• An erbB2 inhibitor as define above may also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the “Background” section, supra.
• CTLA4 antibodies that can be used in the present invention include those described in U.S. Provisional Application 60/113,647 (filed Dec. 23, 1998) which is herein incorporated by reference in its entirety.
• abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (4) any tumors that proliferate by receptor tyrosine kinases; (5) any tumors that proliferate by aberrant serine/threonine kinase activation; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs..
• a small molecule as used herein refers to non-DNA, non-RNA, non-polypeptide and non-monoclonal antibody molecules with a molecular weight of under 1000 AMV. Preferred small molecules are selective for erbB2 over erbB1 at a ratio of at least about 100:1.
• treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
• treatment refers to the act of treating as “treating” is defined immediately above.
• erbB1-sparing means an inhibitor that demonstrates activity against various versions and homologs of the malian erbB2-related kinase, or cells expressing the erbB2 receptor with reduced or no activity against the corresponding erbB1-related kinases or cells. This reduction is expressed in the form of a selectivity ratio as defined previously.
• phrases “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention.
• the compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]
• Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
• Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
• the compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms.
• This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
• the compounds of the present invention may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
• the subject invention also includes isotopically-labelled compounds, and the pharmaceutically acceptable salts, solvates and prodrugs thereof, which are identical to those recited above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, and 36 Cl, respectively.
• Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
• Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• isotopically labelled compounds of identified above and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
• This invention also encompasses pharmaceutical compositions containing and methods of treating bacterial infections through administering prodrugs of compounds of the present invention.
• Compounds of present invention may have free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
• Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention.
• the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters.
• Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
• Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
• acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
• Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
• terminal alkynes may be prepared by a two step procedure. First, the addition of the lithium anion of TMS (trimethylsilyl) acetylene to an appropriately substituted/protected aldehyde as in: Nakatani, K. et. al. Tetrahedron, 49, 9, 1993, 1901. Subsequent deprotection by base may then be used to isolate the intermediate terminal alkyne as in Malacria, M.; Tetrahedron, 33, 1977, 2813; or White, J. D. et. al. Tet. Lett., 31, 1, 1990, 59.
• TMS trimethylsilyl
• pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of convenience.
• the compound of formula 1 may be prepared by coupling the compound of formula D wherein R 4 and R 5 are defined above, with an amine of formula E wherein R 1 , R 3 and R 11 are as defined above, in an anhydrous solvent, in particular a solvent selected from DMF (N,N-dimethylformamide), DME (ethylene glycol dimethyl ether), DCE (dichloroethane) and t-butanol, and phenol, or a mixture of the foregoing solvents, a temperature within the range of about 50-150° C. for a period ranging from 1 hour to 48 hours.
• anhydrous solvent in particular a solvent selected from DMF (N,N-dimethylformamide), DME (ethylene glycol dimethyl ether), DCE (dichloroethane) and t-butanol, and phenol, or a mixture of the foregoing solvents, a temperature within the range of about 50-150° C. for a period ranging from 1 hour to 48 hours.
• heteroaryloxyanilines of formula E may be prepared by methods known to those skilled in the art, such as, reduction of the corresponding nitro intermediates. Reduction of aromatic nitro groups may be performed by methods outlined in Brown, R. K., Nelson, N. A. J. Org. Chem. 1954, p. 5149; Yuste, R., Saldana, M, Walls, F., Tet. Lett. 1982, 23, 2, p. 147; or in WO 96/09294, referred to above. Appropriate heteroaryloxy nitrobenzene derivatives may be prepared from halo nitrobenzene precursors by nucleophilic displacement of the halide with an appropriate alcohol as described in Dinsmore, C. J. et.
• the compound of formula D may be prepared by treating a compound of formula C, wherein Z 1 is an activating group, such as bromo, iodo, —N 2 , or —OTf (which is —OSO 2 CF 3 ), or the precursor of an activating group such as NO 2 , NH 2 or OH, with a coupling partner, such as a terminal alkyne, terminal alkene, vinyl halide, vinyl stannane, vinylborane, alkyl borane, or an alkyl or alkenyl zinc reagent.
• a coupling partner such as a terminal alkyne, terminal alkene, vinyl halide, vinyl stannane, vinylborane, alkyl borane, or an alkyl or alkenyl zinc reagent.
• the compound of formula C can be prepared by treating a compound of formula B with a chlorinating reagent such as POCl 3 , SOCl 2 or ClC(O)C(O)Cl/DMF in a halogenated solvent at a temperature ranging from about 60° C. to 150° C. for a period ranging from about 2 to 24 hours.
• a chlorinating reagent such as POCl 3 , SOCl 2 or ClC(O)C(O)Cl/DMF in a halogenated solvent at a temperature ranging from about 60° C. to 150° C. for a period ranging from about 2 to 24 hours.
• Compounds of formula B may be prepared from a compound of formula A wherein Z 1 is as described above and Z 2 is NH 2 , C 1 -C 6 alkoxy or OH, according to one or more procedures described in WO 95/19774, referred to above.
• Any compound described above can be converted into another compound by standard manipulations to the R 4 group. These methods are known to those skilled in the art and include a) removal of a protecting group by methods outlined in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Second Edition, John Wiley and Sons, New York, 1991; b) displacement of a leaving group (halide, mesylate, tosylate, etc) with a primary or secondary amine, thiol or alcohol to form a secondary or tertiary amine, thioether or ether, respectively; c) treatment of phenyl (or substituted phenyl) carbamates with primary of secondary amines to form the corresponding ureas as in Thavonekham, B et.
• the compounds of the present invention may have asymmetric carbon atoms.
• Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
• the compounds of present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
• the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
• the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
• Those compounds present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
• the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention.
• Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
• salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
• they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
• stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product. Since a single compound of the present invention may include more than one acidic or basic moieties, the compounds of the present invention may include mono, di or tri-salts in a single compound.
• the compounds of the present invention are potent inhibitors of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, in particular erbB2, and thus are all adapted to therapeutic use as antiproliferative agents (eq., anticancer) in mammals, particularly in humans.
• the compounds of the present invention may also be useful in the treatment of additional disorders in which aberrant expression ligand/receptor interactions or activation or signalling events related to various protein tyrosine kinases, are involved.
• Such disorders may include those of neuronal, glial, astrocytal, hypothalamic, and other glandular, macrophagal, epithelial, stromal, and blastocoelic nature in which aberrant function, expression, activation or signalling of the erbB tyrosine kinases are involved.
• the compounds of the present invention may have therapeutic utility in inflammatory, angiogenic and immunologic disorders involving both identified and as yet unidentified tyrosine kinases that are inhibited by the compounds of the present invention.
• DMEM Dulbecco's Minimum Essential Medium
• Test compounds are solubilized in DMSO at a concentration of 10 mM, and tested at final concentrations of 0, 0.3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M and 10 ⁇ M in the medium. The cells are incubated at 37° C. for 2 h.
• EGF (40 ng/ml final) is added to each well and cells incubate at room temperature for 15 min followed by aspiration of medium, then 100 ⁇ l/well cold fixative (50% ethanol/50% acetone containing 200 micromolar sodium orthovanadate) is added. The plate is incubated for 30 min at room temperature followed by washing with wash buffer (0.5% Tween 20 in phosphate buffered saline). Blocking buffer (3% bovine serum albumin, 0.05% Tween 20, 200 ⁇ M sodium orthovanadate in phosphate buffered saline, 100 ⁇ l/well) is added followed by incubation for 2 hours at room temperature followed by two washes with wash buffer.
• wash buffer 3% bovine serum albumin, 0.05% Tween 20, 200 ⁇ M sodium orthovanadate in phosphate buffered saline, 100 ⁇ l/well
• PY54 monoclonal anti-phosphotyrosine antibody directly conjugated to horseradish peroxidase (50 ⁇ l/well, 1 ⁇ g/ml in blocking buffer) or blocked conjugate (1 ⁇ g/ml with 1 mM phosphotyrosine in blocking buffer, to check specificity) is added and the plates incubated for 2 hours at room temperature. The plate wells are then washed 4 times with wash buffer. The colorimetric signal is developed by addition of TMB Microwell Peroxidase Substrate (Kirkegaard and Perry, Gaithersburg, Md.), 50 ⁇ l per well, and stopped by the addition of 0.09 M sulfuric acid, 50 ⁇ l per well.
• Absorbance at 450 nM represents phosphotyrosine content of proteins.
• the increase in signal in EGF-treated cells over control (non-EGF treated) represents the activity of the EGFR or EGFR/chimera respectively.
• the potency of an inhibitor is determined by measurement of the concentration of compound needed to inhibit the increase in phosphotyrosine by 50% (IC 50 ) in each cell line.
• the selectivity of the compounds for erbB2 vs. EGFR is determined by comparison of the IC 50 for the EGFR transfectant vs. that for the erbB2/EGFR chimera transfectant.
• a compound with an IC 50 of 100 nM for the EGFR transfectant and 10 nM for the erbB2/EGFR chimera transfectant is considered 10-fold selective for erbB2 kinase.
• Administration of the compounds of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.
• an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
• the active compound may be applied as a sole therapy or may involve one or more other anti-tumour substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No.
• mitotic inhibitors for example vinblastine
• alkylating agents for example cis-platin, carboplatin and cyclophosphamide
• anti-metabolites for example 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No.
• the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
• the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
• the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
• Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
• Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
• the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
• excipients such as citric acid
• disintegrants such as starch, alginic acid and certain complex silicates
• binding agents such as sucrose, gelatin and acacia.
• lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
• Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
• Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
• the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
• HPLC chromatography is referred to in the preparations and examples below, the general conditions used, unless otherwise indicated, are as follows.
• the column used is a ZORBAXTM RXC18 column (manufactured by Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter.
• the samples are run on a Hewlett Packard-1100 system.
• a gradient solvent method is used running 100 percent ammonium acetate/acetic acid buffer (0.2 M) to 100 percent acetonitrile over 10 minutes.
• the system then proceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutes and then 100 percent buffer solution for 3 minutes.
• the flow rate over this period is a constant 3 mL/minute.
• Et means ethyl
• AC means acetyl
• Me means methyl
• ETOAC or “ETOAc” means ethyl acetate
• THF means tetrahydrofuran
• Bu means butyl.
• Method A Synthesis of [3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine (1):
• Method B Synthesis of 2-Chloro-N-(3- ⁇ 4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl ⁇ -prop-2-ynyl)-acetamide (2):
• Method C Synthesis of 2-Dimethylamino-N-(3- ⁇ 4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl ⁇ -prop-2-ynyl)-acetamide (3):
• Method D Synthesis of 1-(3- ⁇ 4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl ⁇ -prop-2-ynyl)-3-methyl-urea (4):
• Method E Synthesis of 3- ⁇ 4-[3-Methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl ⁇ -prop-2-en-1-ol (5):
• Method F Synthesis of [3-Methyl-4-(pyridin-3-yloxy)-phenyl]-[6-(3-morpholin-4-yl-propenyl)-quinazolin-4-yl]-amine (6):
• E-(3- ⁇ 4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl ⁇ -allyl)-carbamic acid tert-butyl ester To a solution of 7.53 mL of a 65% weight toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 24.2 mmol) in 90 mL of tetrahydrofuran at 0° C.
• E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine To a solution of 4.42 g of E-(3- ⁇ 4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl ⁇ -allyl)-carbamic acid tert-butyl ester in 21 mL of tetrahydrofuran was added 21 mL of 2 N hydrochloric acid. The mixture was heated at 60° C.
• E-N-(3- ⁇ 4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl ⁇ -allyl)-acetamide A mixture of 14.4 ⁇ L (0.25 mmol) of acetic acid and 40.3 mg (0.33 mmol) of dicyclohexylcarbodiimide in 2 mL of methylene chloride were stirred for 10 minutes and treated with 100.3 mg of E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine.
• IC 50 values for the inhibition of erbB1 receptor autophosphorylation and erbB2 receptor autophophorylation were determined using the in vitro cell assays described above.
• the following table shows selectivity of the small molecules for the erbB2 tyrosine kinase versus the erbB1 tyrosine kinase in the form of a ratio of erbB2:erbB1 selectivity ratio.
• the last column shows the potency (IC 50 ) of the each of the small molecules for the erbB2 receptor with the following key: *** ⁇ 20 nM; **21-50 nM; and * is 51-100 nM.

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